Soluble Forms of Intercellular and Vascular Cell Adhesion Molecules Independently Predict Progression to Type 2 Diabetes in Mexican American Families.

Hemant Kulkarni,Sarah Williams-Blangero,Juan Peralta,John Blangero,Thomas D Dyer,David C Glahn,Laura Almasy,Joanne E Curran,Ravindranath Duggirala,Harald H Goring,Marcio Almeida,Manju Mamtani,Rene L Olvera,Michael C Mahaney,Matthew P Johnson,Marta Letizia Hribal

doi:10.1371/journal.pone.0151177

Abstract

ObjectiveWhile the role of type 2 diabetes (T2D) in inducing endothelial dysfunction is fairly well-established the etiological role of endothelial dysfunction in the onset of T2D is still a matter of debate. In the light of conflicting evidence in this regard, we conducted a prospective study to determine the association of circulating levels of soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vessel cell adhesion molecule 1 (sVCAM-1) with incident T2D.MethodsData from this study came from 1,269 Mexican Americans of whom 821 initially T2D-free individuals were longitudinally followed up in the San Antonio Family Heart Study. These individuals were followed for 9752.95 person-years for development of T2D. Prospective association of sICAM-1 and sVCAM-1 with incident T2D was studied using Kaplan-Meier survival plots and mixed effects Cox proportional hazards modeling to account for relatedness among study participants. Incremental value of adhesion molecule biomarkers was studied using integrated discrimination improvement (IDI) and net reclassification improvement (NRI) indexes.ResultsDecreasing median values for serum concentrations of sICAM-1 and sVCAM-1 were observed in the following groups in this order: individuals with T2D at baseline, individuals who developed T2D during follow-up, individuals with prediabetes at baseline and normal glucose tolerant (NGT) individuals who remained T2D-free during follow-up. Top quartiles for sICAM-1 and sVCAM-1 were strongly and significantly associated with homeostatic model of assessment—insulin resistance (HOMA-IR). Mixed effects Cox proportional hazards modeling revealed that after correcting for important clinical confounders, high sICAM-1 and sVCAM-1 concentrations were associated with 2.52 and 1.99 times faster progression to T2D as compared to low concentrations, respectively. Individuals with high concentrations for both sICAM-1 and sVCAM-1 progressed to T2D 3.42 times faster than those with low values for both sICAM-1 and sVCAM-1. The results were similar in women in reproductive age group and the remainder of the cohort. Inclusion of sICAM-1 and sVCAM-1 in predictive models significantly improved reclassification and discrimination. The majority of these results were seen even when the analyses were restricted to NGT individuals.ConclusionSerum concentrations of sICAM-1 and sVCAM-1 independently and additively predict future T2D and represent important candidate biomarkers of T2D.

Highlights

Vascular endothelial dysfunction is a characteristic feature of type 2 diabetes
Decreasing median values for serum concentrations of soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vessel cell adhesion molecule 1 (sVCAM-1) were observed in the following groups in this order: individuals with type 2 diabetes (T2D) at baseline, individuals who developed T2D during follow-up, individuals with prediabetes at baseline and normal
Top quartiles for sICAM-1 and sVCAM-1 were strongly and significantly associated with homeostatic model of assessment—insulin resistance (HOMA-IR)

Summary

Introduction

Vascular endothelial dysfunction is a characteristic feature of type 2 diabetes. An increasing number of studies have shown that the serum concentrations of the adhesion molecules involved in leukocyte adhesion to the endothelial surface are elevated in individuals with T2D as compared to healthy counterparts.[1,2,3,4,5,6,7,8] It appears that the relationship between endothelial dysfunction and T2D may be bidirectional, such that T2D can lead endothelial dysfunction [9, 10] and that endothelial dysfunction can lead to T2D.[11, 12] evidence for endothelial dysfunction preceding or correlating with the risk of later T2D is inconclusive.Meigs and coworkers showed in two large epidemiological studies (using data from the Nurses’ Health Study (737 incident cases of type 2 diabetes and 785 controls) [13] and from Framingham Offspring Study (2,011 diabetes-free individuals) [14]) that adhesion molecules that signify endothelial dysfunction independently predict the risk of future T2D. While the molecular mechanisms for this that directly link endothelial dysfunction and T2D are unclear, it has been posited [19,20,21,22] that endothelial dysfunction may induce insulin resistance and thereby facilitate progression to T2D. This is partly attributable to the endocrine role of the adipose tissue since reversion of the adiponectin:leptin ratio correlates with both insulin resistance and endothelial dysfunction.[23, 24] It has been argued that decreased nitric oxide availability observed in a state of insulin resistance has been correlated with vascular cellular adhesion molecule-1 (VCAM-1) levels.[25]

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Conclusion